Nitrogen-containing heterocyclic compounds and methods of making the same

ABSTRACT

The present invention relates to 7-membered nitrogen-containing heterocyclic compounds and methods of making the same. Using a novel aza-[4+3] cycloaddition reaction, the 7-membered heterocyclic compounds are synthesized by reacting a first reactant and a second reactant. Exemplary first reactants and second reactants include α-halohydroxamates and dienes, respectively.

FIELD OF THE INVENTION

The present invention relates generally to nitrogen-containingheterocyclic compounds and methods of making the same via acycloaddition reaction.

BACKGROUND OF THE INVENTION

The [4+3] cycloaddition reaction of oxyallylcations with dienes has beenintensively studied over the last five decades. This reaction has becomea premier method for the construction of 7-membered carbocycliccompounds and has found numerous applications in target directedsynthesis.

In addition to 7-membered carbocyclic compounds, 7-membered heterocyclicmolecules, such as 7-membered nitrogen-containing heterocycliccompounds, are also of interest as targets possessing useful biologicalactivity or as synthetic intermediates. However, a [4+3] cycloadditionreaction has yet to be developed to prepare 7-memberednitrogen-containing heterocyclic compounds.

Accordingly, a need exists for new 7-membered nitrogen-containingheterocyclic compounds and methods of synthesizing said 7-memberednitrogen-containing heterocyclic compounds.

SUMMARY OF THE INVENTION

This invention relates to nitrogen-containing heterocyclic compounds andmethods of making the same. According to embodiments of the presentinvention, the nitrogen-containing heterocyclic compounds are 7-memberedazacycles that are caprolactam derivatives, which are synthesized via a[4+3] cycloaddition reaction.

According to one embodiment of the present invention, a 7-memberednitrogen-containing heterocyclic compound is provided that isrepresented by the structural formula:

wherein R¹ and R² are the same or different and are independentlyselected from hydrogen, halide, a substituted or un-substituted alkyl,acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or R¹ and R²in combination form a cycloalkyl or a heterocycle; R³ is a substitutedor unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl,cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; R⁴,R⁵, R⁶, and R⁷ are independently selected from hydrogen, halide, asubstituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxyl,acyloxy, thio, or silyl, wherein optionally R⁴ and R⁶, or R⁵ and R⁷combine to form a bridging moiety in a cyclic substructure, the bridgingmoiety including at least one of carbon, oxygen, nitrogen, or sulfur,wherein optionally R⁴ or R⁵ are covalently bonded to R¹ or R², orwherein optionally R⁶ or R⁷ are covalently bonded to R³; and R⁸ and R⁹are independently selected from hydrogen, halide, a substituted orun-substituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl,or R⁸ and R⁹ combine to form a carbon-containing cyclic substructure;and Y is O, S, SO, or NR¹⁰, wherein R¹⁰ is a hydrogen, a substituted orunsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; whereinoptionally R¹⁰ is covalently bonded to R⁶ or R⁷.

According to another embodiment of the present invention, a [4+3]cycloaddition reaction product is provided, wherein the reaction productis derived from a first reactant represented by the general formulaR¹R²XC—CO—NHYR³, wherein R¹ and R² are independently selected fromhydrogen, halide, a substituted or un-substituted alkyl, acyl, aryl,alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino,amido, alkoxy, acyloxy, thio, or silyl, or R¹ and R² in combination forma cycloalkyl or a heterocycle; R³ is a substituted or unsubstitutedalkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, sulfinyl, sulfonyl, or silyl; X is a leaving group; and Yis O, S, SO, or NR¹⁰, wherein R¹⁰ is a hydrogen, a substituted orunsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; and a secondreactant, which is a diene.

According to yet another embodiment of the present invention, a methodof making a nitrogen-containing heterocyclic compound via a [4+3]cycloaddition reaction is provided. The method includes combining afirst reactant, a second reactant, and an activator to form a reactionmixture, and reacting the first reactant and the second reactant to formthe N-containing cycloaddition reaction product. The first reactant hasa chemical formula R¹R²XC—CO—NHYR³, wherein R¹ and R² are independentlyselected from hydrogen, halide, a substituted or un-substituted alkyl,acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or R¹ and R²in combination form a cycloalkyl or a heterocycle; R³ is a substitutedor unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl,cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; X isa leaving group; and Y is O, S, SO, or NR¹⁰, wherein R¹⁰ is a hydrogen,a substituted or unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, orsilyl. The second reactant includes a diene moiety.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Embodiments of the present invention are directed to novel 7-memberedazacyclic compounds and methods of making the same. The compounds maypossess useful biological activity or be useful as intermediates in thetargeted synthesis of biologically active compounds.

A 7-membered nitrogen-containing heterocyclic compound according to oneembodiment of the present invention is represented by the structuralformula (I):

wherein R¹ and R² are independently selected from hydrogen, halide, asubstituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy,acyloxy, thio, or silyl, or R¹ and R² in combination form a cycloalkylor a heterocycle; R³ is a substituted or unsubstituted alkyl, acyl,aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle,sulfinyl, sulfonyl, or silyl; R⁴, R⁵, R⁶, and R⁷ are independentlyselected from hydrogen, halide, a substituted or un-substituted alkyl,acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, whereinoptionally R⁴ or R⁵ and R⁶ or R⁷ combine to form a bridging moiety toform a cyclic substructure, wherein the bridging moiety includes atleast one of carbon, oxygen, nitrogen, or sulfur, wherein optionally R⁴or R⁵ are covalently bonded to R¹ or R², or wherein optionally R⁶ or R⁷are covalently bonded to R³; R⁵ and R⁹ are independently selected fromhydrogen, halide, a substituted or un-substituted alkyl, acyl, aryl,alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino,amido, alkoxy, acyloxy, thio, or silyl, or R⁸ and R⁹ combine to form acarbon-containing cyclic substructure; and Y is O, S, SO, or NR¹⁰,wherein R¹⁰ is a hydrogen, a substituted or unsubstituted alkyl, acyl,aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle,sulfinyl, sulfonyl, or silyl; and wherein optionally R¹⁰ is covalentlybonded to R⁶ or R⁷.

In one embodiment, the 7-membered nitrogen-containing heterocycliccompound can be represented by structural formula (II),

wherein R¹ and R² are independently selected from hydrogen, halide, asubstituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy,acyloxy, thio, or silyl; R³ is a substituted or unsubstituted alkyl,acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, sulfinyl, sulfonyl, or silyl; R⁴ and R⁶ are independentlyselected from hydrogen, halide, a substituted or un-substituted alkyl,acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, whereinoptionally R⁴ is covalently bonded to R¹ or R², or wherein optionally R⁶is covalently bonded to R³; R⁵ and R⁹ are independently selected fromhydrogen, halide, a substituted or un-substituted alkyl, aryl, acyl,alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino,amido, acyloxy, thio, or silyl, or R⁸ and R⁹ combine to form acarbon-containing cyclic substructure; Y is O, S, SO, or NR¹⁰, whereinR¹⁰ is a hydrogen, a substituted or unsubstituted alkyl, acyl, aryl,alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle,sulfinyl, sulfonyl, or silyl; and Z comprises at least one of carbon,oxygen, nitrogen, or sulfur.

In another example, the 7-membered nitrogen-containing heterocycliccompound of formula (I), which may also be referred to as a caprolactamderivative, may be alternatively represented by structural formulas(III) through (VIII).

According to one embodiment of the present invention, the compounds ofstructural formulas (I) through (VIII) can be synthesized by exploitingreactions of a first reactant-derived electrophilic nitrogen species,including an aza-oxyallylcationic intermediate. As shown in Scheme 1, areactive intermediate aza-oxyallylcation (1) can undergo a cyclizationreaction with an appropriate second reactant (2) to synthesize a7-membered nitrogen-containing heterocyclic compound (3), which is aheterocyclic motif that is widely represented in natural products,pharmaceuticals, peptidomimetics, and monomers for polymerization. Thereaction of an aza-oxyallylcation (1) with the second reactant (2),which includes a diene moiety, to form a 7-membered nitrogen-containingheterocyclic compound (3) can be referred to as an aza-[4+3]cycloaddition reaction.

When the second reactant (2) is itself a cyclic diene compound, such ascyclopentadienes, 1,3-cyclohexadienes, pyrroles, or furans, theresultant heterocyclic compound is a bicyclic compound, such as thatshown in the 7-membered nitrogen-containing heterocyclic compound (3).The variables are as defined above. In particular, see the firstreactant for (1); and formula (II) for both (3) and Z in (2).

In accordance with one embodiment of the invention, the requisiteaza-oxyallylcation (1) can be obtained by a dehydrohalogenation of anα-halohydroxamate or its equivalent. Accordingly, α-halohydroxamatesamenable to forming a 7-membered nitrogen-containing heterocycliccompound include those represented by the general formulaR¹R²XC—CO—NHYR³. Accordingly, R¹ and R² are bonded to a carbon atomadjacent a carbonyl, i,e.,the α-carbon, and are independently selectedfrom hydrogen, halide, a substituted or un-substituted alkyl, acyl,aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle,amino, amido, alkoxy, acyloxy, thio, or silyl, or R¹ and R² incombination form a cycloalkyl or a heterocycle. Further, R³ can be asubstituted or unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, orsilyl; X is a leaving group such as a sulfonate (e.g., mesylate ortosylate) or halide; and Y is O, S, SO, or NR¹⁰, wherein R¹⁰ ishydrogen, a substituted or unsubstituted alkyl, acyl, aryl, alkaryl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl,sulfonyl, or silyl.

It should be further appreciated that R³ and/or R¹⁰ may include a chiralmoiety or chiral auxiliary that may induce chirality in the azacycliccycloaddition reaction product.

Any suitable method of preparing the α-halohydroxamate or its equivalentcan be used. For example, α-halo acid halides of a general formulaR¹R²XC—CO—X may be reacted with the appropriate nucleophilic reactant,wherein R¹ and R² are independently selected from hydrogen, halide, asubstituted or un-substituted alkyl, aryl, alkaryl, alkenyl, alkynyl,cycloalkyl, heteroalkyl, or heterocycle, or R¹ and R² in combinationform a cycloalkyl or a heterocycle; X is a halide. For example,2-bromo-2-methylpropanoyl bromide or 2-bromobutyryl bromide are suitableα-halo acid halides. Exemplary nucleophilic reactants include those of ageneral formula NH₂YR³, wherein R³ is a substituted or unsubstitutedalkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, sulfinyl, sulfonyl, or silyl; Y is O, S, SO, or NR¹⁰,wherein R¹⁰ is hydrogen, a substituted or unsubstituted alkyl, acyl,aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle,sulfinyl, sulfonyl, or silyl. For example, O-benzylhydroxylamine orO-methylhydroxylamine are suitable nucleophilic reactants.

As stated above, R³ may comprise a chiral moiety or chiral auxiliarythat may induce chirality in the azacyclic cycloaddition reactionproduct. In the absence of asymmetric induction, the azacycliccycloaddition product is produced as a racemic mixture. As such,according to one embodiment, the nucleophilic reactant of the generalformula NH₂YR³ may include a chiral 3-amino-2-oxazolidone, chiralhydroxylamine derivatives such as(R)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine, chiralhydrazines such as 5-hydrazino-2,4-dinitrophenyl-L-alaninamide, orchiral sulfonamides such as (R)-(+)-2-methyl-2-propanesulfinamide, forexample. In another embodiment, R¹⁰ may comprise a chiral moiety orchiral auxiliary.

Activators are used to effect the dehydrohalogenation of theα-halohydroxamates. Exemplary activators include, but are not limited tobases, such as amine bases and carbonates. Exemplary amine bases,include tertiary amines such as triethylamine or1,4-diazabicyclo[2.2.2]octane (DABCO). Exemplary carbonate bases includealkali metal carbonate salts such as sodium, potassium or cesiumcarbonate. Other useful additives that can be useful in thedehydrohalogenation process include lewis acids, such a lithiumperchlorate. The amount of activator relative to the α-halohydroxamatemay vary. For example, bases such as triethylamine or sodium carbonatemay be used from about one stoichiometric equivalent or more. In oneexample, two (2) stoichiometric equivalents of base were included in theaza-cycloaddition reaction mixture.

Suitable solvents include conventional solvents wherein theα-halohydroxamates are at least partially soluble. Exemplary solventsinclude polar protic, polar aprotic, and non-polar solvents. For polarprotic solvents, it may be advantageous to use halogenated polar proticsolvents to reduce the nucleophilicity of the solvent, which cansuppress undesirable side reactions between the solvent and theα-halohydroxamates. Exemplary halogenated polar protic solvents includetrifluoroethanol (TFE) and hexafluoroisopropanol (HFIP). Other suitablesolvents include diethyl ether, tetrahydrofuran (THF), dichloromethane(DCM), acetonitrile (ACN), nitromethane (MeNO₂), orN-methylpyrrolidinone (NMP), for example. The amount of solvent,relative to the first and second reactants, may be varied to provide adesired concentration of reactants.

According to embodiments of the invention, the second reactant includesa diene compound represented by a general formula R⁴R⁵C═CR⁸—CR⁹═CR⁶R⁷,wherein R⁴, R⁵, R⁶, and R⁷ are independently selected from hydrogen,halide, a substituted or un-substituted alkyl, acyl, aryl, alkaryl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido,alkoxy, acyloxy, thio, or silyl, or wherein optionally (R⁴ or R⁵) and(R⁶ or R⁷) combine to form a bridging moiety to form a cyclicsubstructure, wherein the bridging moiety includes at least one ofcarbon, oxygen, nitrogen, or sulfur; R⁸ and R⁹ are independentlyselected from hydrogen, halide, a substituted or un-substituted alkyl,acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or R⁸ and R⁹combine to form a carbon-containing cyclic substructure. Additionally oralternatively, R⁴ or R⁵ can be covalently bonded to the α-carbon of thefirst reactant through R¹ or R², or that R⁶ or R⁷ can be covalentlybonded to R³ (or R¹⁰ where Y is NR¹⁰) of the first reactant, either ofwhich would yield a complementary bicyclic or tricyclic cycloadditionproduct to that from using acyclic or cyclic dienes, respectively.Exemplary dienes include, but are not limited to, furan,cyclopentadiene, N-substituted pyrroles (e.g., N-acyl, N-sulfonyl,N-alkyl, or N-silyl), or 1,3-cyclopentadiene.

The second reactant, which includes the diene moiety, may also be usedas a co-solvent, if desired. For example, simple and inexpensive dienecompounds, such as cyclopentadiene or furan, may be use as a co-solventthereby providing a large excess of the diene. In one example, furan orcyclopentadiene may be used in 1:1 v/v with the aforementioned solvents.

The method of making a 7-membered azacyclic compound via an aza-[4+3]cycloaddition reaction includes combining the first reactant, the secondreactant, and the activator to form a reaction mixture, and reacting thefirst reactant and the second reactant to form the 7-membered azacyclicreaction product. According to one embodiment of the present invention,the first reactant is a compound represented by the general formulaR¹R²XC—CO—NHYR³; the second reactant includes a diene represented by thegeneral formula R⁴R⁵C═CR⁸—CR⁹═CR⁶R⁷; and the activator may include anamine base or a carbonate salt. The variables are as defined above. Thereacting of the first reactant and the diene reactant is initiated bythe action of activator to effect the dehydrohalogenation of the firstreactant.

The reaction temperatures may range from above the freezing point of thereaction mixture to about the reflux temperature of the reaction mixtureat ambient pressure. If higher temperatures are needed, then thereaction vessel may be pressurized. Accordingly, the reactiontemperature may begin at a first temperature and subsequently changed toa second temperature or a temperature range. For example, the reactantsand activator may be combined at about 0° C. and then passively and/oractively warmed to about 25° C.

The reaction may be performed over a wide temperature range from about0° C. to about 60° C. In one example, the reaction mixture may bemaintained at a temperature of about 15° C. to about 45° C. In anotherexample, the reaction is performed at room temperature. In yet anotherexample, the reaction mixture is first cooled to about 0° C. and thensubsequently warmed to room temperature or above.

While not specifically required, the reaction may be performed under aninert atmosphere. For example, inert gases, such as nitrogen or argon,may be used to purge the reaction vessel prior to charging reagents.Alternatively, the reaction vessel can be maintained under a positivepressure of inert gas over the course of the reaction.

Reaction times may vary depending on a variety of factors, such asreaction temperature, reaction concentration, solvent, nature of theactivator, presence of additives, electronic and/or steric effects ofthe reactants, and the like. Accordingly, the reaction time may be fromabout 15 minutes to about 72 hours, or until at least one of thereactants is substantially consumed. For example, the reaction time maybe from about 0.5 to about 16 hours at room temperature.

The present invention is illustrated by the following examples that aremerely for the purpose of illustration and are not to be regarded aslimiting the scope of the invention or the manner in which it can bepracticed.

General Experimental:

All reactions were carried out under an atmosphere of nitrogen inoven-dried glassware with magnetic stirring, unless otherwise specified.Dichloromethane was purified by passage through a bed of activatedalumina. Cyclopentadiene was distilled from dicyclopentadieneimmediately prior to use. All other reagents and solvents were purchasedfrom Sigma-Aldrich Chemical Company and used without any furtherpurification. Thin-layer chromatography (TLC) information was recordedon Silicycle glass 60 F254 plates and developed by staining with KMnO₄or ceric ammonium molybdate. Purification of reaction products wascarried out by flash chromatography using Silicycle Siliaflash® P60(230-400 mesh). ¹H-NMR spectra were measured on Varian 400 (400 MHz),Varian MR400 (400 MHz), or Varian 500 (500 MHz) spectrometers and arereported in ppm (s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet, br=broad; integration; coupling constant(s) in Hz), usingTetramethylsilane (TMS) as an internal standard (TMS at 0.00 ppm) inCDCl₃ or the solvent peak (1.94 ppm) in CD₃CN. ¹³C-NMR spectra wererecorded on V400 or V500 spectrometer and reported in ppm using solventas an internal standard (CDCl₃ at 77.16 ppm) or (CD₃CN at 118.26 ppm).Infrared (IR) spectra were recorded on a Nicolet 6700 FT-IR with adiamond ATR and data are reported as cm-1 (br=broad, s=strong).High-resolution mass spectra (HRMS) were obtained using an Agilent 6230TOF LC/MS with an (atmospheric pressure photoionization (APPI) orelectrospray (ESI) source with purine and HP-0921 as an internalcalibrants. HRMS data of α-halohydroxamates were obtained with an inlettemperature of 200° C.

The substrate scope of the aza-[4+3] cycloaddition reaction was exploredusing various α-halohydroxamates 4a-k with exemplary diene reactants,e.g., furan or cyclopentadiene. All reactions were conducted insolvent:furan or cyclopentadiene (1:1 v/v, 0.25 M) at 0° C. to 25° C.with triethylamine (TEA) (2.0 equivalents). Trifluoroethanol (TFE) andhexafluoroisopropanol (HFIP) were studied as exemplary solvents.Diastereoisomeric ratio (d.r.) was determined from crude ¹H NMRanalysis. ≧19:1 d.r. indicates that the minor diastereoisomer was notdetected by this analysis. The chemical yield shown in Table 1 is thatof the isolated cycloadduct 5.

TABLE 1 Exemplary aza-[4 + 3] cycloaddition reactions of α-halohydroxamates with cyclopentadiene or furan.

solvent product entry reaction time substrate d.r. (endo:exo) yield^(a)a b c TFE 16 h

R = Me (67%) R = Et (86%) R = t-Bu (54%) d TFE 48 h

78% e TFE 72 h

73% f TFE  1 h

52% g HFIP 30 min

78% h HFIP 30 min

65% i TFE 16 h

85% j TFE 16 h

64% k HFIP 30 min

81% X = O or CH₂

The general procedure (A) for the synthesis of the α-halohydroxamates4a-h is as follows:

To a suspension of the O-benzyloxyamine hydrochloride and triethylamine(TEA) in CH₂Cl₂ (0.25 M) was added dropwise the α-haloacid halide at 0°C. The reaction mixture was stirred at this temperature until TLCanalysis (3:1) hexanes:ethyl acetate (EtOAc) revealed completeconsumption of starting material. The mixture was warmed to roomtemperature and quenched with water. The organic phase was washed 3times with water, dried over sodium sulfate, filtered and evaporated.Purification via recrystallization from hexanes:EtOAc or via a columnchromatography (SiO₂, 3:1, hexanes:EtOAc) provided theα-halohydroxamates in 45-90% yield as a colorless solids.

The general procedure (B) for the aza-[4+3] cycloaddition reaction offuran or cyclopentadiene in trifluoroethanol (TFE) orhexafluoroisopropanol (HFIP) is as follows:

To a solution of α-halohydroxamate (1 equiv) in TFE and furan [1:1 (v/v)0.25 M] or (CF₃)₂CHOH was added TEA (2 equivalents) drop-wise at 0° C.The solution was allowed to warm to room temperature and the reactionprogress was monitored by TLC (3:1 or 2:1 hexanes:EtOAc) until completeconsumption of the α-halohydroxamate. The volatiles were removed underreduced pressure and the residue was purified via flash columnchromatography (4:1 to 3:1, hexanes:EtOAc) to provide the cycloadductsas oils (54-85% yield).

2-bromo-2-methyl-N-(phenylmethyl)propanamide: Prepared in 91% yield(10.7 g, 42 mmol) from the reaction of 2-bromo-2-methylpropanoyl bromide(10.6 g, 46 mmol) with benzylamine (5.1 mL, 46 mmol) via generalprocedure A. Rf=0.84 (3:1, hexanes:EtOAc); mp 73.4-75.5° C.; 1H NMR (400MHz, CDCl3): δ 7.41-7.23 (m, 1H), 7.03 (br s, 1H), 4.46 (d, J=5.8 Hz,1H), and 1.99 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 172.0, 137.8, 128.8,127.6, 127.6, 62.8, 44.4, and 32.6; IR (neat) 3291 (br), 3065, 301,3008, 2938, 2919, 1642 (s), 1533 cm-1; HRMS (ESI) calculated 256.0332C11H15BrNO [M+H]+, observed 256.0329.

(±)-2-bromo-N-(phenylmethoxy)propanamide (4a): Prepared in 53% yield(631 mg, 2.44 mmol) from the reaction of 2-bromo-2-methylpropanoylbromide (1.0 g, 4.6 mmol) with O-benzylhydroxylamine hydrochloride (742mg, 4.6 mmol) via general procedure A. Rf=0.28 (3:1, hexanes:EtOAc);mp=75.3-77.4° C.; 1H-NMR (500 MHz, CDCl3): δ 9.61 (br s, 1H), 7.44-7.26(m, 5H), 4.90 (s, 2H), 4.31 (q, J=7.7 Hz, 1H), and 1.77 (d, J=6.4 Hz,3H); 13C-NMR (126 MHz, CDCl3): δ 167.5, 134.8, 129.45, 128.9, 128.7,78.3, 40.5, and 22.2; FT-IR (neat) 3110 (br), 2924, 2852, 1675 (s),1508, 1495, 1453, 1364, 1188, 1038, 1023 cm-1;

(±)-2-bromo-N-(phenylmethoxy)butanamide (4b, 4i): Prepared in 72% yield(4.71 g, 17.3 mmol) from the reaction of 2-bromobutyryl bromide (5.0 g,24 mmol) with O-benzylhydroxylamine, hydrochloride via general procedureA. Rf=0.49 (3:1, hexanes:EtOAc); mp=99.3-101.6° C.; 1H-NMR (500 MHz,CDCl3): δ 8.92 (br s, 1H), 7.52-7.31 (m, 5H), 4.93 (s, 2H), 4.12 (app q,J=7.2 Hz 1H), 2.02-1.94 (m, 2H), and 1.00 (t, J=7.0 Hz, 3H); 13C-NMR(126 MHz, CDCl3): δ 166.6, 134.8, 129.5, 129.0, 128.7, 78.4, 48.8, 28.8,and 11.8; FT-IR (neat) 3112, 2963, 2933, 2874, 1695, 1668 (s), 1528,1496, 1454, 1364, 1177, 1089, 1023 cm-1. HRMS calculated for C11H15BrNO[M+H]+, 256.0332; found 256.0329.

(±)-2-bromo-2,2-dimethyl N-(phenylmethoxy)butanamide (4c) Prepared in61% yield (3.5 g, 11.8 mmol) from the reaction of2-bromo-2,2-dimethylpropanoyl chloride (4.98 g, 19.3 mmol) withO-benzylhydroxylamine (3.12 g, 19.3 mmol), hydrochloride via generalprocedure A. Rf=0.33 (3:1, hexanes:EtOAc); 1H-NMR (500 MHz, CDCl3): δ8.73 (br s, 1H), 7.55-7.29 (m, 4H), 4.92 (s, 2H), 3.95 (s, 1H), 1.11 (s,9H); 13C-NMR (126 MHz, CDCl3): δ 166.1, 135.0, 129.6, 129.0, 128.8,78.3, 59.4, 35.2, and 27.4; FT-IR (neat): 3179 (br), 3037, 2985, 2960,2944, 2885, 1657 (s), 1511, 1479, 1371, 1241, 1159, 1052 cm-1; HRMSESI-MS calculated for C13H19BrNO2 (M+H)+300.0594, observed 300.0595.

(±)-2-chloro-N-(phenylmethoxy)propanamide (4d): Prepared in 48 yield(0.97 g, 3.9 mmol) from the reaction of 2-chloropropanoyl chloride (1.03g, 8.2 mmol) with O-benzylhydroxylamine, hydrochloride (1.03 g, 8.2mmol) via general procedure A. Rf=0.43 (3:1, hexanes:EtOAc);mp=70.1-72.8° C.; 1H-NMR (500 MHz, CDCl3): δ 9.09 (br s, 1H), 7.44-7.35(m, 5H), 4.93 (s, 4H), 4.33 (q, J=7.1 Hz, 1H), and 1.69 (d, J=6.8 Hz,3H); 13C-NMR (126 MHz, CDCl3): δ 167.1, 134.8, 129.5, 129.1, 128.8,78.5, 53.2, and 22.3.; FT-IR: (neat): 3112 (br), 2931, 1678 (s), 1494,1454, 1364, 1222, 1204, 1074 cm-1. HRMS ESI-MS: calculated forC10H12ClNNaO2 (M+Na)+, 236.0449; found 236.0445.

2,2-dichloro-N-(phenylmethoxy)acetamide (4e, 4j): Prepared in 82 yield(2.6 g, 11.1 mmol) from the reaction of 2,2-dichloroacetyl chloride (2.0g, 13.6 mmol) with O-benzylhydroxylamine, hydrochloride (2.15 g, 13.6mmol) via general procedure A. Rf=0.52 (3:1, hexanes:EtOAc); 1H NMR (400MHz, CD3CN) δ 9.89 (br s, 1H), 7.63-7.17 (m, 4H), 6.02 (s, 1H), and 4.89(s, 2H); 13C NMR (101 MHz, CD3CN) δ 162.2, 136.1, 130.4, 129.7, 129.4,78.8, and 65.6; IR (film) 3135 (br), 2996, 2880, 2860, 1700, 1677 (st),1531, 1468, 1454, 1367, 1341, 1214, 1200, 1046, 1027 cm-1; HR-APPIMScalculated for C9H9Cl2NO2 (M*)+233.0005, observed 232.9976.

(±)-2-chloro-2-(4-chlorophenyl)acetamide (4f): A suspension of theepoxynitrile (315 mg, 1.2 mmol, ˜80% pure) and Obenzylhydroxylaminehydrochloride (240 mg, 1.5 mmol) in acetonitrile (15 mL, 0.1 M) washeated to reflux overnight. The suspension was cooled and the mixturewas concentrated to 5 mL. The residue was partitioned between water andethylacetate and the aqueous phase was extracted (3×15 mL). The combinedorganic phase was washed with brine (15 mL), dried over Na2SO4,filtered, and evaporated under reduced pressure. The residue wasrecrystallized from hexanes and EtOAc to provide the product as acolorless solid (215 mg, 0.69 mmol, 58% yield). Rf=0.20 (3:1,hexanes:EtOAc); 1H NMR (400 MHz, CD3CN) δ 9.76 (s, 1H), 7.51-7.29 (m,9H), 5.27 (s, 1H), and 4.84 (s, 2H). 13C NMR (101 MHz, CD3CN) δ 165.2,136.6, 136.3, 135.5, 130.6, 130.4, 129.8, 129.6, 129.4, 78.6, and 57.9;IR (neat): 3115.8 (br), 2942, 2842, 2662, 1492 (s); HR-ESIMS calculatedfor C15H13Cl2NNaO2 (M+Na)+332.0216, observed 332.0216.

2-bromo-2-methyl-N-(phenylmethoxy)propanamide (4g): Prepared in 87%yield (3.53 g, 11.3 mmol) from the reaction of 2-bromo-2-methylpropanoylbromide (3.0 g, 13 mmol) with O-benzylhydroxylamine hydrochloride (2.13g, 13 mmol) via general procedure A. Rf=0.58 (3:1, hexanes:EtOAc);mp=88.6-91.1° C.; 1H-NMR (500 MHz, CDCl3): δ 9.05 (br s, 1H), 7.45-7.34(m, 5H), 4.94 (s, 2H), and 1.93 (s, 6H); 13C-NMR (126 MHz, CDCl3): δ169.7, 134.9, 129.6, 129.1, 128.8, 78.4, 59.5, and 32.6; FT-IR (neat)3195 (br), 3034, 2954, 2890, 1652 (s), 1505, 1469, 1454, 1112, 1032,1004 cm-1. HRESI-MS: calcd□ for C11H18BrN2O2 (M+NH4)+289.0546, observed289.0543.

(±)-2-bromo-N-(phenylmethoxy)carboxamide (4h, 4k): Prepared in 72% yield(4.5 g, 14.5 mmol) from the reaction of 2-bromocyclohexanoyl bromide(4.53 g, 20.1 mmol) with O-benzylhydroxylamine, hydrochloride (3.21 g,20.1 mmol) via general procedure A. Rf=0.47 (3:1; hexanes:EtOAc);mp=84.6-86.1° C.; 1H NMR (400 MHz, CDCl3) δ 8.98 (br s, 1H), 7.51-7.31(m, 5H), 4.94 (s, 2H), 2.13 (ddd, J=14.6, 10.9, 4.0 Hz, 2H), 2.00 (dt,J=14.0, 4.1 Hz, 2H), 1.80-1.57 (m, 5H), 1.42-1.23 (m, 1H). 13C NMR (101MHz, CDCl3) δ 169.6, 135.0, 129.6, 129.0, 128.7, 78.2, 38.1, 24.7, 22.6.IR (neat) 3235 (br), 3034, 2936, 2862, 1680, 1651 (s), 1470, 1459, 1270,1249, 1210, 1122, 1025, 1000 cm-1; HR-APPIMS calculated for C14H16BrNO2(M+H)+312.0594, observed 312.0206.

(±)-(4S,5R,1S)4-methyl-8-oxo-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one (5a):Prepared in 67% yield (63.3 mg, 0.26 mmol) from the reaction of2-bromo-N-(phenylmethoxy)propanamide (100.7 mg, 0.39 mmol) with furanvia general procedure B. Rf=0.3 (3:1, hexanes:EtOAc); 1H-NMR (500 MHz,CDCl3): δ 7.47-7.32 (m, 5H), 6.57 (dd, J=6.2, 1.0 Hz, 1H), 6.41 (dd,J=6.0, 1.7 Hz, 1H), 5.25 (d, J=1.5 Hz, 1H), 5.00 (d, J=11.0 Hz, 1H),4.87 (d, J=11.0 Hz, 1H), 4.85 (dd, J=5.0, 1.9 Hz, 1H), 3.17 (qd, J=7.4,5.0 Hz, 1H), and 1.09 (d, J=7.4 Hz, 3H); 13C-NMR (126 MHz, CDCl3): δ172.7, 136.1, 135.8, 133.8, 129.7, 128.9, 128.7, 91.6, 82.9, 78.1, 45.1,and 10.6; IR (film) 3089, 2970, 2970, 2934, 2876, 1697, 1497, 1455,1377, 1209, 1053 cm-1; HRMS calculated for C14H16NO3 (M+H)+246.1125,observed 246.1118.

(±)-(4S,5R,1S)4-ethyl-8-oxo-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one (5b):Prepared in 86% yield (40.6 mg, 0.157 mmol) from the reaction of2-bromo-N-(phenylmethoxy)butanamide (50.0 mg, 0.183 mmol) with furan viageneral procedure B. Rf=0.3 (3:1, hexanes:EtOAc); Rf 0.50 (3:1, hexanes:ethyl acetate); 1H-NMR (500 MHz, CDCl3): δ 7.45-7.42 (m, 2H), 7.41-7.32(m, 3H), 6.51 (dd, J=6.0, 1 Hz, 1H), 6.38 (dd, J=6.0, 1.8 Hz, 1H), 5.25(d, J=1.2 Hz, 1H), 4.99 (d, J=11.0 Hz, 1H), 4.95 (dd, J=5.1, 1.8 Hz,1H), 4.87 (d, J=11.0 Hz, 1H), 2.99 (dt, J=10.1, 5.1 Hz, 1H), 2.07-1.96(dqd, J=15.4, 7.5 5.3, 7.5, 15.4 Hz, 1H), 1.24-1.14 (m, 1H), and 1.03(t, J=7.5 Hz, 3H). 13C-NMR (126 MHz, CDCl3): δ 172.1, 135.8, 133.6,129.7, 128.8, 128.6, 91.4, 91.4, 81.3, 78.0, 51.8, 19.5, and 12.3; IR(film) 3250(br), 3032, 2966, 2929, 2877, 1696, 1497, 1455, 1371, 1209,1104, 1055, 1033 cm-1; HR-ESIMS calculated for C15H17NNaO3(M+Na)+282.1101; observed 282.1083.

(±)-(4S,5R,1S)4-(2,2-dimethylethyl)-8-oxo-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one(5c): Prepared in 54% yield (52.7 mg, 0.18 mmol) from the reaction of2-bromo-2,2-dimethyl-N-(phenylmethoxy)propanamide (103.5 mg, 0.34 mmol)with furan via general procedure B. Rf=0.49 (3:1, hexanes:EtOAc); 1H-NMR(500 MHz, CDCl3): δ 7.43 (m, 2H), 7.41-7.33 (m, 3H), 6.42 (dd, J=6.0,1.8 Hz, 2H), 6.35 (dd, J=6.0, 1.5 Hz, 1H), 5.20 (d, J=1.3 Hz, 1H), 5.00(dd, J=4.8, 1.8 Hz, 1H), 4.98 (d, J=11.0 Hz, 1H), 4.88 (d, J=11.0 Hz,1H), 3.04 (d, J=4.8 Hz, 2H), 1.10 (s, 9H); 13C-NMR (126 MHz, CDCl3): δ141.6, 136.0, 134.5, 134.0, 129.8, 128.8, 128.6, 91.6, 81.5, 78.0, 60.5,32.3, and 29.8; IR (film) 3210, 3090, 3064, 3032, 2958, 2871, 1672 (s),1497, 1480, 1455, 1365(s), 1231, 1211, 1162, 1054, 1038 cm-1; HR-ESIMScalculated for C17H21NNaO3 (M+Na)+312.1455, found 312.1446. HRMS:calculated for C17H21NNaO3 (M+Na)+312.1455, found 312.1446

(±)-(4S,5R,1S)4-chloro-8-oxo-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one(endo-5e) and (±)-(4R,5R,1S)4-chloro-8-oxo-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one(exo-5e). Prepared in 73% yield (72 mg, 0.31 mmol) from the reaction of2,2-dichloro-N-(phenylmethoxy)acetamide (100.2 mg, 0.43 mmol) with furanvia general procedure B. Rf=0.50 (3:1, hexanes:EtOAc) 1H NMR (400 MHz,CDCl3) δ 7.51-7.30 (m, 3H), 6.54 (dd, J=6.0, 1.1 Hz, 1H), 6.51 (dd,J=6.0, 1.7 Hz, 1H), 5.27 (d, J=1.1 Hz, 1H), 5.09 (dd, J=5.1, 1.6 Hz,1H), 5.00 (d, J=11.0 Hz, 1H), 4.89 (d, J=11.0 Hz, 1H), and 4.76 (d,J=5.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 165.9, 136.8, 135.3, 133.1,129.8, 129.2, 128.2, 92.1, 82.1, 78.3, and 56.9; IR (film) 3032, 2950,2922, 2852, 1712 (s), 1455, 1369, 1213, 1189, 1059, 1023 cm-1. HR-ESIMScalculated for C13H12ClNNaO3 (M+Na)+288.0398, found 288.0391.exo-diastereoisomer: Rf=0.3 (3:1, hexanes:EtOAc); 1H NMR (400 MHz,CDCl3): δ 7.48-7.35 (m, 2H), 6.68 (d, J=5.9 Hz, 1H), 6.34 (dd, J=6.0,1.1 Hz, 1H), 5.28 (s, 1H), 5.02 (d, J=10.9 Hz, 2H), 4.98 (s, 1H), 4.92(d, J=10.9 Hz, 2H), and 4.09 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 165.5,138.2, 135.0, 131.4, 129.9, 129.2, 128.8, 91.3, 84.2, 78.4, and 56.1; IR(neat) 3067, 3034, 2946, 2885, 1694, 1046 cm-1; HRMS calculated forC13H12ClNNaO3 (M+Na)+288.0398, observed 288.0399.

(±)-(4S,5R,1S)4-(4-chlorophenyl)-8-oxo-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one(5f): Prepared in 53% yield (54.4 mg, 0.16 mmol) from the reaction of2-choro-2-(4-chlorophenyl)-N-(phenylmethoxy)acetamide (95.5 mg, 0.31mmol) with furan via general procedure B. Rf=0.48 (3:1, hexanes:EtOAc);1H-NMR (500 MHz, CDCl3): δ 7.50-7.44 (m, 2H), 7.44-7.34 (m, 3H), 7.28(ABd, J=8.5 Hz, 2H), 7.05 (ABd, J=8.5 Hz, 2H), 6.55 (dd, J=6.0, 1.1 Hz,1H), 6.19 (dd, J=6.0, 1.7 Hz, 1H), 5.36 (d, J=1.3 Hz, 1H), 5.05 (d,J=11.0 Hz, 1H), 4.96 (d, J=11.0 Hz, 1H), 4.94 (dd, J=5.3, 1.8 Hz, 1H),and 4.38 (d, J=5.3 Hz, 1H); 13C-NMR (126 MHz, CDCl3): δ 169.7, 136.0,136.0, 135.6, 133.8, 133.8, 132.0, 131.1, 129.83, 129.1, 128.8, 128.7,91.8, 91.8, 83.1, 83.1, 78.3, and 56.5; IR (film) 3089, 3064, 3031,2924, 1688, 1492, 1454, 1368, 1275, 1260, 1211, 1091, 1059, 1017 cm-1.HR-ESIMS: calculated for C19H17ClNO3 (M+H)+342.0891, observed 342.0886.

(±)-(1R,5S)-4,4-dimethyl-8-oxo-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one(5g): Prepared in 78% yield (85.2 mg, 0.32 mmol) from the reaction of2-bromo-2-methyl N-(phenylmethoxy)propanamide (115.0 mg, 0.42 mmol) withfuran via general procedure B. Rf=0.40 (3:1, hexanes:EtOAc); 1H-NMR (500MHz, CDCl3): δ 7.46-7.28 (m, 5H), 6.56 (dd, J=5.9, 1 Hz, 1H), 6.43 (dd,J=5.9, 1.9 Hz, 1H), 5.21 (d, J=1.1 Hz, 1H), 4.97 (d, J=10.9 Hz, 1H),4.87 (d, J=10.9 Hz, 1H), 4.46 (d, J=1.8 Hz, 1H), 1.49 (s, 3H), and 1.05(s, 3H); 13C-NMR (126 MHz, CDCl3): δ 13C NMR (101 MHz, CDCl3) δ 175.7,135.7, 135.5, 134.6, 129.8, 128.9, 128.6, 91.5, 87.4, 78.0, 49.3, 27.1,and 19.9; IR (film) 3055 (br), ADD MORE, 1692, 1470,1385, 1362, 1265,1217, 1174, 1055, 1008 cm-1; HRMS calculated for C15H17NNaO3(M+Na)+282.1101, observed 282.1098.

(±)-(1′R,5′S)-spiro[cyclohexane-1,2′-[8]oxo-4′-(phenylmethoxy)-4′-azabicyclo[3.2.1]oct[6]en]-3′-one(5h): Prepared in 65% yield (65.9 mg, 0.22 mmol) from the reaction of2-bromo-N-(phenylmethoxy)cyclohexane carboxamide (107.2 mg, 0.34 mmol)with furan via general procedure B. Rf=0.62 (3:1, hexanes:EtOAc); 1H-NMR(500 MHz, CDCl3): δ 7.48-7.29 (m, 5H), 6.54 (d, J=5.8 Hz, 1H), 6.43 (dd,J=6.0, 1.7 Hz, 1H), 5.18 (d, J=1.1 Hz, 1H), 4.96 (d, J=10.9 Hz, 1H),4.93 (d, J=1.4 Hz, 1H), 4.86 (d, J=10.9 Hz, 1H), 2.06 (d, J=12.7 Hz,2H), 1.89 (td, J=13.5, 6.8 Hz, 3H), 1.75 (s, 2H), 1.62 (dd, J=13.3, 7.5Hz, 5H), and 1.47-1.19 (m, 6H); 13C-NMR (101 MHz, CDCl3): δ 175.7,135.8, 135.5, 134.5, 129.8, 128.8, 128.6, 91.2, 82.9, 77.9, 53.3, 33.7,28.9, 25.5, 21.7, and 21.5; IR (film) 3063, 3031, 2927, 2858, 1690,1496, 1454, 1367, 1210, 1187, 1076, 1064 cm-1. HR-ESIMS calculated forC18H21NNaO3 (M+Na)+, 322.1414, observed 322.1424.

(±)-(4S,5R,1S)4-ethyl-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one (endo-5i)and (±)-(4R,5R,1S)4-ethyl-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one (exo-5i):Prepared in 85% yield (82.3 mg, 0.32 mmol) from the reaction of2-bromo-N-(phenylmethoxy)butanamide (100.4 mg, 0.37 mmol) withcyclopentadiene via general procedure B. Rf=0.54 (3:1, hexanes:EtOAc);1H-NMR (500 MHz, CDCl3): δ 7.53-7.28 (m, 5H), 6.30 (dd, J=5.5, 2.0 Hz,1H), 6.12 (dd, J=5.4, 2.7 Hz, 1H), 4.95 (d, J=10.8 Hz, 1H), 4.88 (d,J=10.8 Hz, 1H), 3.90 (d, J=6.1 Hz, 1H), 2.93 (app q, J=4.2 Hz, 1H), 2.59(dt, J=10.4, 4.1 Hz, 1H), 2.09 (dt, J=12.1, 7.8 Hz, 1H), 1.99 (dd,J=11.0, 5.3 Hz, 1H), 1.85 (d, J=10.8 Hz, 1H), 1.37-1.16 (m, 2H), and1.01 (t, J=7.5 Hz, 3H). 13C-NMR (101 MHz, CDCl3): δ 171.6, 137.2, 137.0,136.0, 129.8, 129.7, 128.7, 128.5, 77.19, 64.5, 51.5, 42.4, 40.8, 21.6,and 12.3; IR (film) 3063, 3031, 2961, 2874, 1668 (s), 1455, 1368.HR-ESIMS: calculated C16H19NaO2 (M+Na)+280.1308, found 280.1296.exodiastereoisomer (characterized as a mixture 2.5:1 exo:endo) Rf=0.41(3:1, hexanes:EtOAc); 1H NMR (500 MHz, CDCl3): d 7.5-7.3 (m, 5H), 6.30(dd, J=5.5, 2.5 Hz, 1H), 6.17 (dd, J=5.5, 2.9 Hz, 1H), 4.93 (d, J=10.7Hz, 1H), 4.86 (d, J=10.7 Hz, 1H), 3.86 (br s, 1H), 2.73 (app t, J=4.2Hz, 1H), 2.20 (dd, J=10.1, 5.3 Hz, 1H), 2.12-2.16 (m, 1H), 2.05-1.98 (m1H), 1.92 (d, J=11.3 Hz, 1H), 1.74 (ddd, J=10, 5, 5 Hz, 1H), 1.62-1.59(m, 1H), 1.31-1.18 (m, 1H), and 1.05 (t, J=7.1 Hz, 3H); 13C NMR (101MHz, CDCl3) δ 174.5, 138.3, 136.4, 136.0, 129.9, 128.8, 128.5, 77.0,64.4, 51.5, 42.2, 38.8, 34.3, 30.5, 25.7, 21.6, and 21.3. IR (film)3063, 3031, 2961, 2874, 1679, 1496, 1455, 1370 cm-1; HRMS calculatedC16H19NaO2 (M+Na)+280.1308, found 280.1303.

(±)-(4S,5R,1S)4-chloro-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one and(±)-(4R,5R,1S)4-chloro-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one (5j):Prepared in 64% yield (73.8 g, 0.28 mmol) from the reaction of2-bromo-N-(phenylmethoxy)butanamide (100.8 mg, 0.43 mmol) withcyclopentadiene via general procedure B. Rf=0.53 (3:1, hexanes:EtOAc);1H-NMR (500 MHz, CDCl3): δ 7.46-7.34 (m, 3H), 6.32 (dd, J=5.7, 2.2 Hz,1H), 6.31-6.28 (m, 1H), 4.98 (d, J=10.9 Hz, 1H), 4.92 (d, J=10.9 Hz,1H), 4.71 (d, J=4.4 Hz, 1H), 2.06 (dt, J=11.6, 4.8 Hz, 1H), and 1.90 (d,J=11.5 Hz, 1H); 13C-NMR (126 MHz, CDCl3): δ 164.7, 138.0, 136.5, 135.5,129.9, 129.0, 128.6, 77.4, 65.0, 61.0, 46.8, and 41.7; IR (film) 3066,3033, 2926, 2853, 1679, 1455, 1372 cm-1; HR-ESIMS calculated forC14H15ClNO2 (M+H)+264.0786, found 264.0779.

(±)-(1′R,5′S)spiro[cyclohexane-1,2′-4′-(phenylmethoxy)-4′-azabicyclo[3.2.1]oct[6]en]-3′-one(5k): Prepared in 81% yield (72.9 mg, 0.26 mmol) from the reaction of2-bromo-N-(phenylmethoxy)butanamide (100.4 mg, 0.32 mmol) withcyclopentadiene via general procedure B. Rf=0.6 (3:1, hexanes:EtOAc);1H-NMR (400 MHz, CDCl3): 7.42 (d, J=7.5 Hz, 2H), 7.40-7.29 (m, 3H), 6.25(dd, J=5.6, 2.0 Hz, 1H), 6.16 (dd, J=5.6, 2.9 Hz 1H), 4.92 (d, J=10.4Hz, 2H), 4.88 (d, J=10.3 Hz, 2H), 3.84 (dd, J=4.2, 3.5 Hz, 1H), 2.98(dd, J=4.1, 3.1 Hz, 1H), 1.98 (d, J=11.2 Hz, 1H), 1.94 (dt, J=16.6, 12.6Hz, 1H) 1.88-1.84 (m, 1H), 1.83 (dt, J=10.6, 4.5 Hz, 1H), 1.75 (dq,J=13.4, 3.6 Hz, 1H), 1.70-1.60 (m, 3H), 1.55-1.42 (m, 2H), and 1.42-1.31(m, 2H); 13C NMR (101 MHz, CDCl3) δ 174.5, 138.6, 136.4, 136.0, 130.0,128.7, 128.5, 77.0, 64.4, 51.5, 42.3, 38.8, 34.3, 30.5, 25.7, 21.6, and21.3; IR (film) 3062, 3030, 2925, 2858, 1662 (s), 1454, 1371 cm-1.HRESIMS calculated for C19H24NNaO2 (M+Na)+321.1699, observed 321.1651.

2-methyl-2-(2,2,2-trifluoroethoxy)-N-(phenylmethoxy)-propanamide:Produced as a by-product 56% from the reaction of2-bromo-2-methyl-N-(phenylmethoxy)propanamide with TEA in furan andtrifluoroethanol. Rf=0.26 (3:1, hexanes:EtOAc); 1H NMR (500 MHz, CDCl3)δ 8.88 (s, 1H), 7.56-7.31 (m, 5H), 4.94 (s, 2H), 3.68 (q, J=8.3 Hz, 2H),1.43 (s, 6H); 13C NMR (125 MHz, CDCl3) 13C NMR (101 MHz, cdcl3) δ 170.8,134.9, 129.4, 129.0, 128.7, 123.7 (q, J=278 Hz), 80.4, 78.3, 61.6 (q,J=35 Hz), and 23.6; FT-IR 3218 (br), 3036; 2942, 2886, 1663 (st), 1430,1455, 1485, 1386, 1369, 1307, 1285, 1217, 1181, 1145, 1029, 1010 cm-1;HR-ESIMS calculated for C13H17F3NO3 (M+H)+292.1155, observed 292.1160.

2-methyl-N-(phenylmethoxy)-2-propenamide: Elimination product from thereaction attempted cycloaddition of 4g with LiClO₄/Et₃N in diethylether. 1H NMR (400 MHz, CDCl3) δ 8.19 (br s, 1H), 7.49-7.29 (m, 5H),5.55 (pent, J=1 Hz, 1H), 5.32 (dq, J=1.6, 1.0 Hz, 1H), 4.96 (s, 2H), and1.92 (dd, J=1.6, 1.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.2, 138.0,135.4, 129.5, 129.0, 128.8, 120.4, 78.3, and 18.6; IR (film) 3199 (br),3064, 3032, 2954, 2878, 1658, 1620, 1496, 1453, 1372, 1322, 1209, 1039cm-1; HR-ESIMS calculated for C11H13NNaO2 (M+Na)+215.0871, found215.0869.

Mono-alkyl substituted bromohydroxamates (entries a-e, Table 1) providedthe highest yields of the cycloadduct under the recited conditions. Withthe exception of entry e (R¹═Cl), all mono-substituted halohydroxamates(entries a-d and f) selectively provided the endo-diastereoisomer (≧19:1by crude 1H NMR analysis). In the case of entry e, a diasteriomericratio of the cycloaddition was observed to vary over the course of thereaction; at early conversion (ca. 40% conversion), a diasteriomericratio of ≧19:1 d.r. was observed, but at 100% conversion, thediasteriomeric ration was ca. 2:1, endo:exo. Treatment of the pureendo-adduct to the reaction conditions provided an epimeric mixture (ca.1:1, endo:exo) after 24 h, suggesting that the α-stereogenic center ofthe endo-product is epimerizing during the reaction. The monosubstitutedhydroxamates were slower to react and did not solvolyze intrifluoroethanol. Changing the halogen from bromide to chlorideultimately provided a comparable yield of the product after 48-72 h(entries e and f). Unsubstituted mono-bromohydroxamate (X═Br, R¹═R2=H)was found to be un-reactive under these conditions. This result isconsistent insofar as the un-substituted oxyallylcation does not havethe added stabilization afforded by groups such as alkyl substituents,and the dehydrohalogenation of α-bromoacetamide also did not result in a[4+3] cycloaddition with furan. In constrast, fully-substituted andaryl-substituted α-halohydroxamates rapidly reacted under the conditionsto provide the corresponding cycloadduct in moderate yield. The bestresults for these fully-substituted and aryl-substitutedα-halohydroxamates were observed in HFIP (entries f-h). The increase inrate of conversion of these substrates is presumably due to thestabilizing effect that substitution (R¹═R²=alkyl, entries g and h) ordelocalization (entry f) has on the aza-oxyallylcationic intermediate.

The aza-[4+3] cycloaddition of α-halohydroxamates with cyclopentadieneafforded the cycloadducts in comparable yield to the corresponding furanreactions (entries i-k, Table 1). The ethyl-substitutedα-halohydroxamate provided the cyclopentadiene aza-[4+3] cycloadduct inidentical yield but with less diastereoselectivity than its reactionwith furan (entry i). The aza-[4+3] cycloaddition reaction of theα,α-dichlorohydroxamate with cyclopentadiene provided a mixture ofdiastereoisomeric cycloadducts at full conversion (8:1, entry j) ofstarting material. Again, the reaction time of the bromo-cyclohexanehydroxamate was considerably shorter than what was observed for thereaction of the ethyl-substituted hydroxamate (cf entry i and k, Table1).

With reference now to Table 2 below, the effect of solvent and thenature/amount of the activator was further explored with respect tocompound 4g from Table 1.

TABLE 2 Effect of solvent and activator on the yield of the aza-[4 + 3]cycloaddition reaction of 2-bromobutyramide 4g with furan.

Entry^(a) Solvent Activator Yield^(b) % 1 TFE Et₃N  38%^(c) 2 HFIP Et₃N78% 3 HFIP Cs₂CO₃ 58% 4 HFIP K₂CO₃ 67% 5 HFIP Na₂CO₃ 74% 6 TFE imidazoledecomp. 7 TFE pyridine no reaction 8 Et₂O Et₃N, LiClO₄ See text ^(a)Allreactions were conducted in solvent:furan (1:1 v/v, 0.25 M) at 0° C.with activator (2.0 equiv) ^(b)Isolated yield of the cycloadduct 5g.^(c)Provided a 56% yield of CF₃CH₂OH solvolysis product.

The treatment of the α-bromohydroxamate 4g to Fölisch-type [4+3]cycloaddition conditions (TFE/TEA) in the presence of furan resulted ina rapid consumption of starting material, providing a 38% yield of thedesired cycloadduct 5. A trifluoroethylether 6 (56%) was formed as themajor product of this reaction, and presumed to be the result ofsolvolysis of the intermediate or the N-benzyloxyaziridinone. The choiceof activator and solvent influences the yield of the cycloadduct.Changing to hexafluoroisopropanol (HFIP) as the solvent slowed theformation of the solvolysis product and significantly improved the yieldof the cyclcoadduct (cf entry 1 with 2-5, Table 2); the iso-propyl ether6 was not detected by crude ¹H NMR analysis. Various amine bases, withthe exception of pyridine and imidazole, were found to successfullyinduce the desired cycloaddition reaction. Carbonate bases worked well,all providing desired product in comparable yield (entries 3-5, Table 2)to the reaction using triethylamine. The reaction could be effected inether by using triethylamine with lithium perchlorate as a Lewis-acidadditive, but these conditions also provided a methacrylamide 7 as themajor product from the elimination of the cationic intermediate or atransient α-lactam.

As demonstrated herein, α-halohydroxamates such as N-benzyloxyα-bromoamides react under basic conditions with cyclic dienes to providebicyclic lactams in good yield. Without being bound by any particulartheory, one plausible mechanism is that an aza-oxyallylcationicintermediate is formed upon dehydrohalogenation of theα-halohydroxamates and that this aza-oxyallylcationic intermediateundergoes an aza-[4+3] cycloaddition reaction with dienes. Theheteroatom-substitution on the nitrogen group is presumed to stabilizethe aza-oxyallylcationic intermediate.

The aza-[4+3] cycloadducts are suitable intermediates for the synthesisof biologically-active molecules. For example, the aza-[4+3]cycloadducts are suitable intermediates for the synthesis ofnitrogen-containing compounds, such as balanol which possesses potentprotein kinase C inhibition activity (see Boros, C. et al., J. Antibiot.1994, 47, 1010), and banisternosides A and B which possess MAOinhibitory and antioxidative activities relevant to neurodegenerativedisorders and Parkinson's disease (see Samoylenko, V. et al. J.Ethnopharm. 2010, 127, 357), as well as analogues and/or derivativesthereof. Other exemplary targets include anti-viral carbocyclicnucleosides such as carbovir, aristeromycin and BMS-200475, orglycosidase inhibitors such as deoxynojirimycin, miglitol, andpoly-hydroxylated azepanes, obtainable from the aza-[4+3] cycloadductsof α-halohydroxamates with cyclopentadiene and furan, respectively.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. As well, the terms “a” (or “an”), “one or more” and “at leastone” can be used interchangeably herein. It is also to be noted that theterms “comprising”, “including”, “characterized by” and “having” can beused interchangeably.

While the present invention has been illustrated by the description ofone or more embodiments thereof, and while the embodiments have beendescribed in considerable detail, they are not intended to restrict orin any way limit the scope of the appended claims to such detail.Additional advantages and modifications will readily appear to thoseskilled in the art. The invention in its broader aspects is thereforenot limited to the specific details, representative product and/ormethod and examples shown and described. The various features ofexemplary embodiments described herein may be used in any combination.Accordingly, departures may be made from such details without departingfrom the scope of the general inventive concept.

1. A 7-membered nitrogen-containing heterocyclic compound represented bystructural Formula (I):

wherein R¹ and R² are the same or different and are independentlyselected from hydrogen, halide, a substituted or un-substituted alkyl,acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or R¹ and R²in combination form a cycloalkyl or a heterocycle; R³ is a substitutedor unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl,cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; R⁴,R⁵, R⁶, and R⁷ are the same or different and are independently selectedfrom hydrogen, halide, a substituted or un-substituted alkyl, acyl,aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle,amino, amido, alkoxy, acyloxy, thio, or silyl, wherein optionally R⁴ andR⁶, or R⁵ and R⁷ combine to form a bridging moiety in a cyclicsubstructure, the bridging moiety including at least one of carbon,oxygen, nitrogen, or sulfur, wherein optionally R⁴ or R⁵ are covalentlybonded to R¹ or R², or wherein optionally R⁶ or R⁷ are covalently bondedto R³; and R⁸ and R⁹ are the same or different and are independentlyselected from hydrogen, halide, a substituted or un-substituted alkyl,acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or R⁸ and R⁹combine to form a carbon-containing cyclic substructure; and Y is O, S,SO, or NR¹⁰, wherein R¹⁰ is a hydrogen, acyl, a substituted orunsubstituted alkyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; whereinoptionally R¹⁰ is covalently bonded to R⁶ or R⁷.
 2. A [4+3]cycloaddition reaction product of a first reactant represented bygeneral formula R¹R²XC—CO—NHYR³, wherein R¹ and R² are the same ordifferent and independently selected from hydrogen, halide, asubstituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy,acyloxy, thio, or silyl, or R¹ and R² in combination form a cycloalkylor a heterocycle; R³ is a substituted or unsubstituted alkyl, acyl,aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle,sulfinyl, sulfonyl, or silyl; X is a leaving group; and Y is O, S, SO,or NR¹⁰, wherein R¹⁰ is a hydrogen, a substituted or unsubstitutedalkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, sulfinyl, sulfonyl, or silyl; and a second reactant havinga diene moiety.
 3. A method of making a 7-membered nitrogen-containingheterocyclic compound via a [4+3] cycloaddition reaction, the methodcomprising: combining a first reactant, a second reactant, and anactivator to form a reaction mixture, the first reactant represented bygeneral formula R¹R²XC—CO—NHYR³, wherein R¹ and R² are the same ordifferent and are independently selected from hydrogen, halide, asubstituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy,acyloxy, thio, or silyl, or R¹ and R² in combination form a cycloalkylor a heterocycle; R³ is a substituted or unsubstituted alkyl, acyl,aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle,sulfinyl, sulfonyl, or silyl; X is a leaving group; and Y is O, S, SO,or NR¹⁰, wherein R¹⁰ is a hydrogen, a substituted or unsubstitutedalkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,heterocycle, sulfinyl, sulfonyl, or silyl; the second reactant having adiene moiety; and reacting the first reactant and the second reactant inthe presence of the activator to form the nitrogen-containingheterocyclic compound.